The goal of this project is to establish a strategy that will make neuronal electrical signaling detectable via magnetic resonance imaging (MRI) at a whole-brain level. Our approach is built on the novel concept of using cell-adhesive micron-scale electronic devices to transduce neuronal potentials across the brain into magnetic field fluctuations. As part of our validation of these voltage-sensing microprobes, we also propose to implement a new, scalable method for simultaneous recording of MRI and electrophysiological data. The methods we propose to develop will be broadly applicable to problems in neurobiology, and will transform neuroscientists'ability to study integrative functions of the brain. Our microprobe approach will also help establish a new paradigm in diagnostic medicine and molecular imaging, where tiny machines, rather than conventional chemical contrast agents, will report on aspects of cellular physiology. Recent work has dem- onstrated that micron-scale electrodes, coated with cell-adhesive molecules and juxtaposed against cultured cells allow recording of millivolt-scale action potentials, comparable to intracellular recordings. The current induced in a microelectrode can be converted into a modest, transient magnetic field if it is channeled into an inductor. In Specific Aim 1, we will model the magnetic fields produced by feasible currents in spiral or solenoidal microcoils of defined geometry, compute predicted effects on MRI signal amplitude and phase as a function of microprobe distribution, and fabricate the microprobes themselves. Preliminary calculations indicate that localized, transient fields of about 10 nT could be produced in individual 10-turn microcoils of 1 5m diameter. Magnetic fields of this order are greater than endogenous neuronal fields detected in tech- nologies like magnetoencephalography, and have been shown previously to be measurable by MRI in some contexts. In Specific Aim 2, we will test the ability of our microprobes to report action potentials from neu- ronal populations in MRI. The microdevices wil first be applied to cultured neurons or neural tissue slices and placed in an MRI scanner. Data series will be obtained using multiple protocols to detect variations of MRI signal due to variations in neuronal activity. If experiments in culture are successful, microprobes will be site-specifically injected into the cerebral cortex of anesthetized rats, and tested in an somatosensory stimu- lation paradigm. In Specific Aim 3, we will establish a simultaneous MRI and conventional electrophysiology approach to validate the novel MRI voltage probes directly. Performing electrophysiology in an MRI scanner is complicated by artifacts induced by the scanning hardware, in particular due to switched gradient fields. To circumvent this problem, we will measure neuronal potentials using differential recording from pairs of channels on tetrodes or modified tetrodes. Once the in-scanner recording method has been refined, MRI- based and conventional electrophysiology data will be obtained and compared to assess performance of the voltage-sensing microprobes, and to guide further improvements, if necessary. PUBLIC HEALTH RELEVANCE: Noninvasive MRI-based electrophysiology using microelectronic devices will have high impact in biology, and specifically in brain research, both through applications to the study of neurological disease and as tools for the analysis of neural network function in basic neuroscience. The microprobes we propose to develop represent a new paradigm in diagnostic medicine, where tiny machines, rather than conventional chemical contrast agents, will report on aspects of cellular physiology.